Phenylene derivatives

ABSTRACT

This invention relates to a phenylene derivative represented by the following formula (1) or a salt thereof and also to a medicine containing it as an effective ingredient. ##STR1## wherein R 1  represents H or halogen; A represents --CH═CH--, --CH═N--, --N(R 2 )--, --O-- or --S--; W represents --CH═CH-- or --CH 2  O--; X represents --CH 2  O--, --CH 2  S--, --CH 2  N(R 3 )--, --CH═N--, --COO-- or --CONH--; Y represents ##STR2## B 1  represents --C(R 7 )(R 8 )(CH 2 ) l  --, --S(O) m  (CH 2 ) n  -- or --CH═C(R 9 )--; B 2  represents --CH 2  CH 2  -- or --CH 2  CH 2  CH 2  --; Z 1  and Z 2  each represents O or S; etc. The phenylene derivative or salt thereof has antileukotrienic action and antihistaminic action and is useful as a medicine such as an asthma preventive or curative.

BACKGROUND OF THE INVENTION

a) Field of the Invention

This invention relates to phenylene derivatives or salts thereof, whichare useful as medicines.

b) Description of the Related Art

Leukotrienes (LT) are associated with causes for most inflammatorydiseases, especially asthma, psoriasis, rheumatism and inflammatorycolitis, and are considered to play an important role in inflammatoryprocesses through cytopathy. Leukotrienes are principal mediators ofallergy and inflammation, and therefore many substances which inhibitthe action and/or syntheses of leukotrienes are useful for the treatmentof these diseases.

Leukotrienes are arachidonate metabolites synthesized by 5-lipoxygenase(5-LO), and consist of two groups. One of the groups is LTB₄ and hasstrong chemotaxis towards leukocytes. The other group is collectivelycalled cysteine leukotrienes (CysLT) and includes LTC₄, LTD₄ and LTE₄.As biologically active substances, they have been called "slow-reactingsubstances of anaphylaxis (SRS-A)" for many years. CysLT binds to theirreceptors in human tissues to exert its action. A selective LTD₄receptor inhibitor has been found to inhibit contracting actions of bothLTC₄ and LTD₄ in human lung tissues, so that LTC₄ is suggested to bindto the same site of a receptor as LTD₄ (Buckner C. K. et al: Ann. NYAcad. Sci., 524, 181-6, 1988; Aharony D. et al.: New Trends in LipidMediators Research, Basel: Karger 67-71, 1989). LTE₄ is also consideredto act via the same receptor as LTD₄, but is called a partially activesubstance for its lower potency.

On the other hand, histamine exhibits bronchial smooth muscleconstricting action and capillaropenetration accelerating action as aresult of its binding to the H₁ receptor in cell membranes, and is animportant mediator in allergic diseases. Histamine is believed to causeaggravation of asthmatic symptoms by its bronchoconstricting action andalso to increase transudation of blood components into intercellularspacings due to accelerated capillaropenetration and hence to take partin the formation of edema seen in allergic rhinitis and conjunctivitis.For the treatment of these allergic diseases, antihistaminic agents aretherefore used. These antihistaminic agents are however not consideredto be significantly effective for severe allergic diseases such asasthma. Especially in a late asthmatic response of asthma, the symptomof airway constriction which is typical to asthma is observed due toinfiltration of inflammatory cells on the bronchial mucosa,oversecretion of mucus and the like. Pharmaceuticals of a new type aretherefore desired for its treatment.

Described specifically, a severe allergic disease such as asthma isconsidered to develop, as successive morbid conditions, an immediateasthmatic response such as bronchial constriction and edematousformation, in which a mediator such as histamine takes principal part,and a late asthmatic response such as airway constriction due to cellinfiltration and mucus secretion in which a leukotriene or the liketakes part.

For the prevention or curation of a variety of allergic diseases,especially asthma, a compound having antagonism against both an LTD₄receptor and a histamine H₁ receptor is considered to become aneffective pharmaceutical.

In addition to such marked peripheral action, leukotrienes have alsobeen reported to have certain relevance to causes for cerebropathy suchas cerebral ischemia and cerebral apoplexy (Masamune H. and Melvin L.S.: Ann. Rep. Med. Chem., 24, 71-79, 1989). It has also been reportedthat upon occurrence of procepharic ischemia, the concentration of LTC₄produced in neurocytes arises in the hippocampus (13.37±0.24pmol/g-tissue) and the cerebral cortex (3.29±1.09 pmol/g) (Ohtsuki T. etal.: Am. J. Physiol., 37, H1249-57, 1995). Further, it has also beenreported that intravenous administration of FPL55712, an LTD₄antagonist, after occurrence of ischemia significantly inhibitedincrease and aggravation of cortical edema (Watanabe T. et al.: J.Pharmacol. Exp. Ther., 271, 1624-29, 1994).

Accordingly, leukotriene receptor antagonistic compounds are consideredto become effective pharmaceuticals for such cerebropathy.

It is however the current circumstances that no compound has been foundwith fully satisfactory antagonism against both an LTD₄ receptor and ahistamine H₁ receptor. Further, all the LTD₄ antagonists which have beendeveloped so far contain at least one acidic group, so that these LTD₄antagonists are hydrophilic compounds having high polarity. They arethus unavoidably insufficient in absorption and brain penetration uponinhalative administration or oral administration. This is believed tohave led to the increased doses of these pharmaceuticals and hence, tothe development of side effects.

SUMMARY OF THE INVENTION

Therefore, an object of the present invention is to provide a medicinecomprising as an effective ingredient a compound having bothantileukotrienic action and antihistaminic action, and another object ofthe present invention is to provide a medicine comprising as aneffective ingredient a strong leukotriene receptor antagonisticcompound.

With the foregoing current circumstances in view, the present inventorshave conducted an extensive investigation with a view to obtaining astrong leukotriene receptor antagonistic compound which has bothantileukotrienic action and antihistaminic action. As a result, it hasbeen found that a compound represented by the following formula (1) isuseful, leading to the completion of the present invention.

In one aspect of the present invention, there is accordingly provided aphenylene derivative represented by the following formula (1) or a saltthereof: ##STR3## wherein

R¹ represents a hydrogen atom or a halogen atom,

A represents --CH═CH--, --CH═N--, ##STR4## --O-- or --S--, R² being alower alkyl group or an alkoxyalkyl group,

W represents --CH═CH-- or --CH₂ O--,

X represents --CH₂ O--, --CH₂ S--, ##STR5## --CH═N--, --COO-- or--CONH--, R³ being a hydrogen atom or a lower alkyl group,

Y represents the following formula (a), (b) or (c): ##STR6##

wherein

R⁴ is a hydrogen atom or a lower alkyl group,

B¹ represents ##STR7## and R⁸ each being a hydrogen atom or a loweralkyl group, R⁹ being a hydrogen atom, a cyano group, a halogen atom, acarboxyl group or a tetrazolyl group, l and m being a value of from 0 to2, and n being a value of 1 to 2,

R⁵ represents a hydrogen atom or a lower alkyl group,

Z¹ represents an oxygen atom or a sulfur atom,

B² represents --CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --,

R⁶ represents a hydrogen atom or a lower alkyl group,

Z² represents an oxygen atom or a sulfur atom, or Z² and R⁶ are coupledtogether with the adjacent nitrogen atom to form a tetrazolyl group.

In another aspect of the present invention, there is also provided amedicine comprising as an effective ingredient a phenylene derivativerepresented by the formula (1) or a salt thereof.

In a further aspect of the present invention, there is also provided amedicinal composition comprising a phenylene derivative represented bythe formula (1) or a salt thereof and a pharmaceutically acceptablecarrier.

In a still further aspect of the present invention, there is alsoprovided a method for treating an allergic disease such as asthma,allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticariaor psoriasis, rheumatism, inflammatory colitis, cerebral ischemia orcerebral apoplexy, which comprises administering an effective amount ofa phenylene derivative represented by the formula (1) or a salt thereofto a patient.

The phenylene derivative (1) or the salt thereof according to thepresent invention has antileukotrienic action and antihistaminic actionand is useful as a medicine such as asthma preventive or curative.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

In compound (1), examples of the halogen atoms represented by R¹ and R⁹include fluorine, chlorine, bromine and iodine atoms, among which achlorine atom is preferred.

Illustrative of the lower alkyl groups represented by R², R³, R⁴, R⁵,R⁶, R⁷ and R⁸ are alkyl groups having 1-6 carbon atoms. These alkylgroups include both linear and branched alkyl groups. More preferredalkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, pentyl and n-hexyl, with methyl and n-hexyl beingparticularly preferred.

Illustrative of the alkoxyalkyl group represented by R² are C₁₋₆ alkoxyC₁₋₆ alkyl groups, specifically methoxymethyl, methoxyethyl,methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl,ethoxybutyl, propoxymethyl, propoxyethyl, propoxypropyl andpropoxybutyl, with ethoxyethyl being particularly preferred.

Examples of the group represented by the formula (a) include groupsrepresented by the following formula (a-1) to formula (a-7). ##STR8##wherein R⁴, R⁵, R⁷, R⁸, R⁹, Z¹ and m have the same meanings as definedabove.

Further, examples of the group represented by the formula (b) includegroups represented by the following formula (b-1) and formula (b-2).##STR9## wherein Z², R⁴ and R⁶ have the same meanings as defined above.

No particular limitation is imposed on the salt of the compound (1) ofthe present invention, insofar as it is a pharmacologically acceptablesalt. Illustrative are mineral acid addition salts such as thehydrochloride, hydrobromide, hydroiodide, sulfate and phosphate; organicacid addition salts such as the benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate,fumarate, tartrate and citrate; and metal salts such as the sodium salt,potassium salt, calcium salt, magnesium salt, manganese salt, iron saltand aluminum salt.

Further, the compound (1) of the present invention may also exist in theform of solvates represented by the hydrate. Such solvates are alsoincluded in the present invention.

The compound (1) of the present invention can be prepared, for example,in accordance with the following reaction scheme. ##STR10## wherein Y'represents ##STR11## R^(3') represents a lower alkyl group, E representsan oxygen atom or NH, and R¹, R⁴, R⁵, R⁶, Z¹, Z², A, B¹, B² and W havethe same meanings as defined above.

Namely, subsequent to the conversion of the compound (2) into thechlorinated derivative (3), the chlorinated derivative (3) is reactedwith the phenol compound (4) to obtain the compound (5). On the otherhand, the chlorinated derivative (3) and the aldehyde compound (6) aresubjected to a Witting reaction so that the compound (5') is obtained.This compound (5) or compound (5') is converted into the chlorinatedderivative (8), followed by the reaction with the compound (9) to obtainthe invention compound (1a). By sulfurizing the compound (1a), theinvention compound (1b) is obtained. Further, the compound (8') isobtained from the compound (3), which is then reacted with the compound(9') to obtain the invention compound (1c). In addition, the compound(3) and the hydroxybenzaldehyde compound (11) are reacted to obtain theinvention compound (1d). Reduction of the compound (1d) then providesthe invention compound (1e), whose alkylation in turn provides theinvention compound (1f).

Incidentally, as the compound (2), compound (9) and compound (9'),either conventionally known compounds or those prepared byconventionally known processes can be used.

A description will next be made about the individual steps of the abovereaction scheme.

Step 1

The compound (3) is obtained by reacting the compound (2) with an excessamount of SOCl₂ in an inert solvent such as THF (tetrahydrofuran), CHCl₃or CH₂ Cl₂ at a temperature of from 0° C. to reflux temperature(preferably at room temperature) for 1 to 24 hours.

Step 2

The compound (5) is obtained by reacting equimolar amounts of thecompound (3) and the compound (4) in the presence of an excess amount ofa base such as K₂ CO₃ or Na₂ CO₃ in a polar solvent such as DMF(N,N-dimethylformamide), DMSO (dimethylsulfoxide) or HMPA(hexamethylphosphoramide) at a temperature of from 0° C. to refluxtemperature (preferably at room temperature to 60° C.) for 1 to 7 days.

Step 3

The compound (3) is refluxed together with an equimolar amount of PPh₃("Ph" stands for a phenyl group) in an inert solvent such as benzene,toluene or xylene for 12 to 48 hours to synthesize the correspondingphosphonium salt. The phosphonium salt is reacted with an equimolaramount of t-BuOK (potassium tertbutoxide) in dry THF under a nitrogen orargon gas stream to prepare a Wittig reagent, to which an equimolaramount of the compound (6) is added, followed by refluxing for 1 to 12hours to obtain the compound (7).

Step 4

The compound (5') is obtained by reacting the compound (7) with NaBH₄ ina polar solvent such as methanol or ethanol at a temperature of from 0°C. to reflux temperature (preferably at room temperature) for 1 to 24hours.

Step 5

The compound (8) is obtained by reacting the compound (5) or thecompound (5') with an excess amount of SOCl₂ in an inert solvent such asTHF, CHCl₃ or CH₂ Cl₂ at a temperature of from 0° C. to refluxtemperature (preferably at room temperature) for 1 to 24 hours.

Step 6

The invention compound (1a) is obtained by reacting equimolar amounts ofthe compound (8) and the compound (9) in the presence of an excessamount of a base such as K₂ CO₃ or Na₂ CO₃ in a polar solvent such asDMF, DMSO or HMPA at a temperature of from 0° C. to reflux temperature(preferably at room temperature to 60° C.) for 1 to 7 days.

Step 7

The compound (1b) is obtained by reacting the compound (1a) with asulfurizing agent such as P₂ S₅ or the Lawesson's reagent in an inertsolvent such as benzene, toluene or xylene at reflux temperature for 1to 6 hours.

Step 8

The methyl ester derivative of the compound (8') is obtained by reactingequimolar amounts of the compound (3) and the compound (10) in thepresence of an excess amount of a base such as K₂ CO₃ or Na₂ CO₃ in apolar solvent such as DMF, DMSO or HMPA at a temperature of from 0° C.to reflux temperature (preferably at room temperature to 60° C.) for 1to 7 days. The methyl ester derivative is reacted with 2 to 4equivalents of NaOH in water-containing MeOH for 1 to 12 hours, wherebythe compound (8') is obtained.

Step 9

The invention compound (1c) is obtained by reacting equimolar amounts ofthe compound (8') and the compound (9') in the presence of a couplingagent such as DCC (N,N'-dicyclohexylcarbodiimide) or WSC.HCl in a polarsolvent such as DMF, DMSO or HMPA at a temperature of from 0° C. toreflux temperature (preferably at room temperature to 60° C.) for 1 to14 days.

Step 10

The aldehyde compound (8") is obtained by reacting equimolar amounts ofthe compound (3) and the compound (11) in the presence of a base such asK₂ CO₃, Na₂ CO₃ or triethylamine and a phase transfer catalyst such astetrabutylammonium bromide or tetraethylammonium bromide in a polarsolvent such as DMF, DMSO or HMPA at a temperature of from 0° C. toreflux temperature (preferably at room temperature to 60° C.) for 1 to14 days.

Step 11

The invention compound (1d) is obtained by reacting equimolar amounts ofthe compound (8") and the compound (9") in a polar solvent such asethanol, methanol, butanol, DMF, DMSO or HMPA at a temperature of from0° C. to reflux temperature (preferably at room temperature to 100° C.)for 1 to 14 days.

Step 12

The invention compound (1e) is obtained by reacting the compound (1d)further in one of polar solvents such as methanol, ethanol, DMF, DMSO,HMPA or a mixed solvent thereof (preferably in a mixed solvent of DMFand methanol) in the presence of a reducing agent, for example, NaBH₄ at0° C. to 60° C. (preferably at 0° C. to room temperature) for 30 minutesto 24 hours.

Step 13

The invention compound (1f) is obtained by reacting the compound (1e)further with an alkyl halide in the presence of a base such as K₂ CO₃,Na₂ CO₃ or triethylamine and a phase transfer catalyst such astetrabutylammonium bromide or tetraethylammonium bromide in a polarsolvent such as DMF, DMSO or HMPA at a temperature of from 0° C. toreflux temperature (preferably at room temperature to 60° C.) for 1 to14 days.

Further, to obtain the invention compound (1a) or (1c) in which B is--(O)_(m') CH₂ -- or --S(O)_(m') CH₂ CH₂ -- (m': 1 or 2) in the formula(1) from the compound (1a) or (1c) in which B is --SCH₂ -- or --SCH₂ CH₂-- in the formula (1), it is only necessary to react the compound (1a)or (1c) with m-CPBA or H₂ O₂ in a molar amount 1 or 2 times as much asthe compound (1a) or (1c) in a solvent such as CHCl₃, CH₂ Cl₂ or AcOH(Ac: acetyl group) at 0° C. to room temperature for 1 to 72 hours.

The above-described target compounds can each be obtained by treatingthe reaction mixture by a method known per se in the art and ifnecessary, can be purified using a conventional purification method suchas column chromatography. By a method known per se in the art, they canbe converted into the above-described desired salts as needed.

As will be demonstrated subsequently in Examples, the invention compound(1) or salt thereof available as described above has excellentantileutrienic action and antihistaminic action, and is useful as amedicine such as a preventive or curative for asthma, allergic rhinitis,allergic conjunctivitis, atopic dermatitis, urticaria, psoriasis,rheumatism, inflammatory colitis, cerebral ischemia or cerebralapoplexy.

The medicine according to the present invention comprises theabove-described compound (1) or a salt or hydrate thereof as aneffective ingredient. Its administration forms include, for example,oral administration forms such as tablets, capsules, granules, powdersand syrups; and parenteral administration forms such as intravenousinjections, intramuscular injections, suppositories, inhalative agents,percutaneous absorption agents, eye drops and nasal drops. Uponproduction of medicinal preparations in such various administrationforms, the effective ingredient can be used either singly or by suitablycombining the same with one or more pharmacologically acceptablevehicles such as excipients, binders, extenders, disintegrants,surfactants, lubricants, dispersants, buffers, preservatives,corrigents, perfumes, coating materials, carriers, diluents and thelike.

The dosage of the medicine according to the present invention variesdepending on the age, body weight, conditions, administration form,administration frequency and the like. In general, however, it ispreferred to orally or parenterally administer to an adult the effectiveingredient in an amount of about 1 to 1,000 mg per day at once or inseveral portions.

The present invention will next be described in further detail by thefollowing Examples. It should however be borne in mind that the presentinvention is by no means limited to these Examples.

PREPARATION EXAMPLE 1

Synthesis of 3-(2-quinolinylmethoxy)benzyl chloride

SOCl₂ (2 ml) was added to a solution of 3.58 g (13.5 mmol) of3-(2-quinolinylmethoxy)benzyl alcohol in 100 ml of CHCl₃, followed bystirring at room temperature for 24 hours. A small amount of MeOH wasadded to the reaction mixture and the solvents were distilled off underreduced pressure, whereby the title compound was obtained as whitepowder.

EXAMPLE 1

Synthesis of 3-cyano-6-3-(2-quinolinylmethoxy)-benzyloxy!-1,2-dihydroquinolin-2-one

3-(2-quinolinylmethoxy)benzyl chloride (3.49 g, 12.3 mmol) was added toa solution of 2.45 g (12.3 mmol) of3-cyano-6-hydroxy-1,2-dihydroquinolin-2-one in 100 ml of DMF, followedby the further addition of 2.04 g (14.8 mmol) of K₂ CO₃ and 396 mg (1.23mmol) of tetra-n-butylammonium bromide. The resulting mixture wasstirred under an argon gas stream at room temperature for 24 hours. Thereaction mixture was concentrated under reduced pressure, followed bythe addition of CHCl₃ --MeOH and water to extract the reaction productinto the organic layer. The organic layer was dried over Na₂ SO₄ andthen concentrated under reduced pressure. The residue was subjected tochromatography on a silica gel column. Subsequent to elution with CHCl₃,recrystallization was conducted from a CHCl₃ --MeOH mixed solvent,whereby 250 mg of the title compound were obtained as yellow powder(yield: 4.7%).

Melting point: 145°-147° C. (decomposed).

¹ H-NMR(CDCl₃ --MeOH)δ(ppm): 5.31(2H,s,--C₆ H₄ --CH₂ --), 5.51(2H,s,C₉H₆ N--CH₂ --), 6.74(1H,br,Ar-H), 6.83-7.00(3H,m,Ar-H),7.09-7.31(3H,m,Ar-H), 7.56-7.64(2H,m,Ar-H), 7.79(1H,ddt,J=8.5,7.1,1.5Hz,Ar-H), 7.88(1H,d,J=8.1 Hz,Ar-H), 8.03(1H,d,J=8.8 Hz,Ar-H),8.18(1H,s,Ar-H), 8.20(1d,d,J=8.8 Hz,Ar-H).

IR(KBr)cm⁻¹ : 3059, 2225, 1648, 1613, 1569, 1451, 1252, 1070, 774.

EXAMPLES 2-17

The following compounds were obtained in a similar manner as in Example

                  TABLE 1                                                         ______________________________________                                        Ex.   Compound (1)         mp(°C.)                                     ______________________________________                                        2     8-Methyl-5- 3-(2-quinolinylmethoxy)-                                                               205-207                                                  benzyloxy!-1,2-dihydroquinolin-2-one                                    3     3-Cyano-8-methyl-5- 3-(2-quinolinyl-                                                               224-225                                                  methoxy)benzyloxy!-1,2-dihydro-                                               quinolin-2-one                                                          4     2-Chloro-8-methyl-5- 3-(2-quinolinyl-                                                              217-219                                                  methoxy)benzyloxy!-1,2-dihydro-                                               quinolin-2-one                                                          5     8-Methyl-5- 3-(2-quinolinylmethoxy)-                                                               172-174                                                  benzyloxy!-1,2,3,4-tetrahydro-                                                quinolin-2-one                                                          6     6- 3-(2-Quinolinylmethoxy)benzyloxy-                                                               158-159                                                  1,2,3,4-tetrahydroquinolin-2-one                                                                   (dec)                                              7     7- 3-(2-Quinolinylmethoxy)benzyloxy-                                                               180-183                                                  1,2,3,4-tetrahydroquinolin-2-one                                                                   (dec)                                              8     8- 3-(2-Quinolinylmethoxy)benzyloxy!-                                                              124-125                                                  1,2,3,4-tetrahydroquinolin-2-one                                        9     7- 3-(2-Quinolinylmethoxy)benzyloxy!-                                                              150-151                                                  2,3,4,5-tetrahydrobenz b!azepin-2-one                                   10    7- 3-(2-Quinolinylmethoxy)benzyloxy!-                                                              160-162                                                  3,4-dihydro-2H-1,4-benzothiazin-3-                                            one                                                                     11    8- 3-(2-Quinolinylmethoxy)benzyloxy!-                                                              139-140                                                  2,3,4,5-tetrahydro-1,5-benzo-                                                 thiazepin-4-one                                                         12    4- 3-(2-Quinolinylmethoxy)benzyloxy!-                                                              193-195                                                  2,3-dihydro-1H-indol-2-one                                              13    4- 3-(2-Quinolinylmethoxy)benzyloxy!-                                                              178-180                                                  3,3,7-trimethyl-2,3-dihydro-1H-                                               indol-2-one                                                             14    3,3'-Dimethyl-5- 3-(2-quinolinyl-                                                                  162-163                                                  methoxy)benzyloxy!-2,3-dihydro-1H-                                            indol-2-one                                                             15    3,3-Dimethyl-6- 3-(2-quinolinyl-                                                                   161-162                                                  methoxy)benzyloxy!-2,3-dihydro-1H-                                            indol-2-one                                                             16    3,3-Dimethyl-4-(n-hexyl)-6- 3-(2-                                                                  117-119                                                  quinolinylmethoxy)benzyloxy!-2,3-                                             dihydro-1H-indol-2-one                                                  17    3,3-Dimethyl-7- 3-(2-quinolinyl-                                                                   136-139                                                  methoxy)benzyloxy!-2,3-dihydro-1H-                                                                 (dec)                                                    indol-2-one                                                             ______________________________________                                    

PREPARATION EXAMPLE 2

Synthesis of 4-(2-quinolinylmethoxy)benzyl Chloride

In a similar manner as in Preparation Example 1, the title compound wasobtained as white powder from 4-(2-quinolinylmethoxy)benzyl alcohol.

EXAMPLE 18

Synthesis of 3,3-dimethyl-5-4-(2-quinolinylmethoxy)benzyloxy!-2,3-dihydro-1H-indol-2-one

4-(2-Quinolinylmethoxy)benzyl chloride (567 mg, 2 mmol) was dissolved in20 ml of DMF, followed by the addition of 354 mg (2 mmol) of3,3-dimethyl-5-hydroxy-2,3-dihydro-1H-indol-2-one, 64 mg (0.2 mmol) oftetra-n-butylammonium bromide and 691 mg (5 mmol) of K₂ CO₃. Theresultant mixture was stirred under an argon gas stream at 50° C. for 72hours. After the solvent was distilled off, water was added, and thethus-formed mixture was extracted twice in a CHCl₃ --MeOH (3:1) mixedsolvent. The extract was dried over MgSO₄ and then concentrated underreduced pressure. The residue was subjected to chromatography on asilica gel column. Subsequent to elution with CHCl₃, recrystallizationwas conducted from AcOEt-hexane, whereby 199 mg of the title compoundwere obtained as pale yellow powder (yield: 23.5%).

Melting point: 172°-175° C. (decomposed).

¹ H-NMR(CDCl₃)δ(ppm): 1.37(6H,s,C3-Me×2), 4.94(2H,s,--C₆ H₄ --CH₂ --),5.40(2H,s,C₉ H₆ N--CH₂ --), 6.78-6.80(2H,m,Ar-H), 6.85(1H,d,J=2.2Hz,Ar-H), 7.02(2H,d,J=8.8 Hz,--C₆ H₄ --CH₂ --), 7.36(2H,d,J=8.8 Hz,--C₆H₄ --CH₂ --), 7.55(1H,dt,J=8.1,1.5 Hz,Ar-H), 7.67(1H,d,J=8.6 Hz,Ar-H),7.74(1H,dt,J=8.5,1.5 Hz,Ar-H), 7.83(1H,d,J=8.1 Hz,Ar-H), 8.09(1H,d,J=8.5Hz,Ar-H), 8.20(1H,d,J=8.5 Hz,Ar-H), 8.29(1H,brs,CONH).

IR(KBr)cm⁻¹ : 1727, 1613, 1601, 1515, 1493, 1456, 1429, 1382, 1301,1277, 1251, 1224, 1196, 1174, 1115, 1072, 1062, 1027, 1013, 952, 934,903, 872, 832, 804, 785, 754, 651, 619, 535, 525, 477, 460.

EXAMPLES 19-30

In a similar manner as in Example 18, the following compounds wereobtained.

                  TABLE 2                                                         ______________________________________                                        Ex.   Compound (1)         mp(°C.)                                     ______________________________________                                        19    3-Cyano-8-methyl-5- 4-(2-quinolinyl-                                                               267-270                                                  methoxy)benzyloxy!-1,2-dihydro-                                                                    (dec)                                                    quinolin-2-one                                                          20    3-Chloro-8-methyl-5- 4-(2-quinolinyl-                                                              253-256                                                  methoxy)benzyloxy!1,2-dihydro-                                                                     (dec)                                                    quinolin-2-one                                                          21    8-Methyl-5- 4-(2-quinolinylmethoxy)-                                                               193-195                                                  benzyloxy!-1,2,3,4-tetrahydro-                                                                     (dec)                                                    quinolin-2-one                                                          22    6- 4-(2-Quinolinylmethoxy)benzyloxy-                                                               186-189                                                  1,2,3,4-tetrahydroquinolin-2-one                                        23    7- 4-(2-Quinolinylmethoxy)benzyloxy-                                                               199-202                                                  1,2,3,4-tetrahydroquinolin-2-one                                        24    8- 4-(2-Quinolinylmethoxy)benzyloxy!-                                                              133-134                                                  1,2,3,4-tetrahydroquinolin-2-one                                        25    7- 4-(2-Quinolinylmethoxy)benzyloxy!-                                         2,3,4,5-tetrahydro-1H-benzo b!azepin-                                                              181-183                                                  2-one                                                                   26    7- 4-(2-Quinolinylmethoxy)benzyloxy!-                                                              229-232                                                  3,4-dihydro-2H-1,4-benzothiazin-3-                                                                 (dec)                                                    one                                                                     27    4- 4-(2-Quinolinylmethoxy)benzyloxy!-                                                              209-211                                                  3,3,7-trimethyl-2,3-dihydydro-1H-                                             indol-2-one                                                             28    3,3-Dimethyl-6- 4-(2-quinolinyl-                                                                   191-196                                                  methoxy)benzyloxy!-2,3-dihydro-1H-                                                                 (dec)                                                    indol-2-one                                                             29    3,3-Dimethyl-4-(n-hexyl)-6- 4-(2-                                                                  134-136                                                  quinolinylmethoxy)benzyloxy!-2,3-                                             dihydro-1H-indol-2-one                                                  30    3,3-Dimethyl-7- 4-(2-quinolinyl-                                                                   150-153                                                  methoxy)benzyloxy!-2,3-dihydro-1H-                                                                 (dec)                                                    indol-2-one                                                             ______________________________________                                    

PREPARATION EXAMPLE 3

Synthesis of 3-(7-chloro-2-quinolinylmethoxy)benzyl chloride

In a similar manner as in Preparation Example 1, the title compound wasobtained from 3-(7-chloro-2-quinolinylmethoxy)benzyl alcohol.

EXAMPLE 31

Synthesis of 7-3-(7-chloro-2-quinolinylmethoxy)benzyloxy!-1,2,3,4-tetrahydroquinolin-2-one

A mixture of 0.326 g (2 mmol) of7-hydroxy-1,2,3,4-tetrahydroquinolin-3-one, 0.609 g (5 mmol) of K₂ CO₃,0.075 g (0.25 mmol) of tetra-n-butylammonium bromide, 40 ml of DMF and0.636 g (2 mmol) of 3-(7-chloro-2-quinolinylmethoxy)benzyl chloride wasstirred at room temperature for 3 days. Insoluble matter was removed andthe solvent was then distilled off. The residue was subjected tochromatography on a silica gel column. Subsequent to elution with CHCl₃,recrystallization was conducted from acetone, whereby 0.245 g of thetitle compound was obtained as pale yellow powder (yield: 27.6%).

Melting point: 150°-151° C.

¹ H-NMR(CDCl₃)δ(ppm): 2.53-2.67(2H,m,CH₂ at C3), 2.81-2.94(2H,m,CH₂ atC4), 5.00(2H,s,--C₆ H₄ --CH₂), 5.37(2H,s,C₉ H₅ NCl--CH₂ --),6.36(1H,d,J=2.4 Hz,C8-H), 6.55(1H,dd,J=8.8,2.4 Hz,C6-H),6.91-7.14(4H,m,Ar-H), 7.32(1H,d,J=7.8 Hz,Ar-H), 7.50(1H,dd,J=8.8,1.9Hz,Ar-H), 7.67(1H,d,J=8.8 Hz,Ar-H), 7.76(1H,dd,J=8.8,1.9 Hz,Ar-H),8.04(1H,brs,CONH), 8.07(1H,d,J=1.9 Hz,Ar-H), 8.16(1H,d,J=8.3 Hz,Ar-H).

IR(KBr)cm⁻¹ : 1681, 1628, 1614, 1595, 1521, 1492, 1375, 1274, 1198,1184, 852.

EXAMPLE 32

Synthesis of 7-3-(7-chloro-2-quinolinylmethoxy)benzyloxy!-3,4-dihydro-2H-1,4-benzothiazin-3-one

In a similar manner as in Example 31, the title compound was obtained asyellow powder from 7-hydroxy-3,4-dihydro-2H-1,4-benzothiazin-3-one(yield: 42.9%).

Melting point: 163°-165° C. (CHCl₃)

¹ H-NMR(DMSO-d₆)δ(ppm): 3.42(2H,s,CH₂ -- at C2), 5.03(2H,s,--C₆ H₄ --CH₂O), 5.38(2H,s,CH₂ O--C₆ H₄ --), 6.73-7.05(5H,m,Ar-H), 7.13(1H,s,Ar-H),7.31(1H,t,J=7.8 Hz,Ar-H), 7.60-7.74(2H,m,Ar-H), 7.98-8.12(2H,m,Ar-H),8.46(1H,d,J=8.8 Hz,Ar-H), 10.40(1H,s,CONH).

IR(KBr)cm⁻¹ : 3190, 3083, 3045, 2963, 2909, 1671(CONH), 1613, 1587,1498, 1290, 1270, 1238, 1156, 1068, 842, 766.

PREPARATION EXAMPLE 4

Synthesis of 3-(2-quinazolinylmethoxy)benzyl alcohol

To a solution of 5.00 g (28 mmol) of 2-chloromethylquinazoline in 50 mlof DMF, 4.26 g (31 mmol) of K₂ CO₃ and 903 mg (2.8 minol) oftetra-n-butylammonium bromide were added. 3-Hydroxybenzyl alcohol (3.48g, 28 mmol) was added further, followed by stirring at room temperaturefor 5 days. The reaction mixture was concentrated under reducedpressure, followed by the addition of CHCl₃ and water to extract thereaction product into the organic layer. The extract was dried over Na₂SO₄ and then concentrated under reduced pressure. The residue wasrecrystallized from a CHCl₃ -n-hexane mixed solvent, whereby 6.4 g ofthe title compound was obtained as pale yellow powder (yield: 93.1%).

Melting point: 92°-96° C.

¹ H-NMR(CDCl₃)δ(ppm): 4.65(2H,s,--C₆ H₄ --CH₂ --OH), 5.46(2H,s, C₈ H₅ N₂--CH₂ --), 6.96(1H,d,J=7.8 Hz,--C₆ H₄ --), 6.99(1H,d,J=7.8 Hz,--C₆ H₄),7.11(1H,s,--C₆ H₄ --), 7.25(1H,dd,J=7.8,7.8 Hz,--C₆ H₄ --),7.67(1H,dd,J=7.5,7.5 Hz,C ₈ H₅ N₂ --), 7.93(1H,dd,J=9.0,7.5 Hz,C₈ H₅N₂), 7.95(1H,d,J=7.5 Hz,C₈ H₅ N₂ --), 8.07(1H,d,J=9.0 Hz,C₈ H₅ N₂ --),9.43(1H,s,C₈ H₅ N₂ --).

IR(KBr)cm⁻¹ : 3328, 1621, 1613, 1582, 1441, 1378, 1292, 1077, 752.

EXAMPLE 33

Synthesis of 73-(2-quinazolinylmethoxyl)-benzyloxy!-3,4-dihydro-2H-1,4-benzothiazin-3-one

To a solution of 1.00 g (3.76 mmol) of 3-(2-quinazolinylmethoxy)benzylalcohol in 10 ml of CHCl₃, 0.5 ml of SOCl₂ was added, followed bystirring at room temperature for 15 hours. A small amount of MeOH wasadded to the reaction mixture and the solvents were distilled off underreduced pressure, whereby 1.08 g of 3-(2-quinazolinylmethoxy)benzylchloride were obtained as white powder.

It was added to a solution of 567 mg (31.3 mmol) of7-hydroxy-3,4-dihydro-2H-1,4-benzothiazin-3-one, followed by the furtheraddition of 600 mg (47.0 mmol) of K₂ CO₃ and 99.9 mg (3.1 mmol) oftetra-n-butylammonium bromide. The resultant mixture was stirred underan argon gas stream at room temperature for 7 days. The reaction mixturewas concentrated under reduced pressure, and CHCl₃ and water were addedto the residue to extract the reaction product into the organic layer.The extract was dried over Na₂ SO₄ and then concentrated under reducedpressure. The residue was subjected to chromatography on a silica gelcolumn. Subsequent to elution with CHCl₃, recrystallization wasconducted from a CHCl₃ -n-hexane mixed solvent, whereby 858 mg of thetitle compound was obtained as pale brown acicular crystals (yield:53.2%).

Melting point: 167°-170° C.

¹ H-NMR(CDCl₃)δ(ppm): 3.39(2H,s,--SCH₂ CONH--), 4.99(2H,s,--C₆ H₄ --CH₂--), 5.47(2H,s,C₈ H₅ N₂ --CH₂ --), 6.67(1H,d,J=8.8 Hz,--C₈ H₆ NOS--),6.74 (1H,dd,J=8.8,2.6 Hz,C₈ H₆ NOS--), 6.87(1H,d,J=2.6 Hz,C₈ H₆ NOS--),6.89-6.99(2H,m,--C₆ H₄ --), 7.13(1H,s,--C₆ H₄ --), 7.28(1H,dd,J=8.0,8.0Hz,--C₆ H₄ --), 7.58-7.66(2H,m,C₈ H₅ N₂ --,NH), 7.93 (1H,dd,J=9.0,7.5Hz,C₈ H₅ N₂ --), 7.95(1H,d,J=7.8 Hz,C₈ H₅ N₂ --), 8.07(1H,d,J=9.0 Hz,C₈H₅ N₂ --), 9.44(1H,s,C₈ H₅ N₂ --).

IR(KBr)cm⁻¹ : 2905, 1670, 1502, 1383, 1267, 1231, 1043, 834, 775, 749.

EXAMPLE 34

Synthesis of 7-3-(2-quinazolinylmethoxy)benzyloxy!-1,2,3,4-tetrahydroquinolin-2-one

In a similar manner as in Example 33, the title compound was obtained asyellow powder from 7-hydroxy-1,2,3,4-tetrahydroquinolin-2-one (yield:31.1%).

Melting point: 178°-180° C. (acetone)

¹ H-NMR(CDCl₃)δ(ppm): 2.53-2.67(2H,m,CH₂ at C3), 2.81-2.94(2H,m,CH₂ atC4), 5.00(2H,s,--C₆ H₄ --CH₂ --), 5.48(2H,s,C₈ H₅ N₂ --CH₂ --),6.34(1H,d,J=2.4 Hz,C8-H), 6.55(1H,dd,J=8.3,2.4 Hz,C6-H),6.95-7.05(3H,m,Ar-H), 7.13-7.18(1H,m,Ar-H), 7.23-7.34(2H,m,Ar-H),7.68(1H,td,J=8.0,1.2 Hz,Ar-H), 7.80(1H,brs,CONH), 7.90-8.00(2H,m,Ar-H),8.08(1H,d,J=9.0 Hz,Ar-H), 9.45(1H,s,Ar-H).

IR(KBr)cm⁻¹ : 1672, 1593, 1520, 1488, 1389, 1370, 1261, 1196, 1169,1012, 785, 767.

EXAMPLE 35

Synthesis of 7-4-(2-quinazolinylmethoxy)benzyloxy!-1,2,3,4-tetrahydroquinolin-2-one

In a similar manner as in Example 33, the title compound was obtained asyellow prismatic crystals from 4-(2-quinazolinymethoxy)benzyl chlorideand 7-hydroxy-1,2,3,4-tetrahydroquinolin-2-one (yield: 38.6%).

Melting point: 178°-180° C. (acetone)

¹ H-NMR(CDCl₃)δ(ppm): 2.52-2.66(2H,m,CH₂ at C3), 2.79-2.95(2H,m,CH₂ atC₄), 4.93(2H,s,--C₆ H₄ --CH₂ --), 5.48(2H,s,C₈ H₅ N₂ --CH₂ --),6.37(1H,d,J=2.4 Hz,C8-H), 6.58(1H,dd,J=8.3,2.4 Hz,C6-H),6.94-7.14(3H,m,C₆ H₄ --), 7.32(2H,d,J=8.8 Hz,C₆ H₄ --),7.60-7.73(1H,m,Ar-H), 7.87-8.00(3H,m,Ar-H,CONH), 8.08(1H,d,J=9,3Hz,Ar-H), 9.45(1H,s,Ar-H).

IR(KBr)cm⁻¹ : 1670, 1624, 1595, 1515, 1487, 1375, 1244, 1165, 1018.

PREPARATION EXAMPLE 5

Synthesis of 3-(N-methylbenzimidazol-2-ylmethoxy)benzyl alcohol

In a similar manner as in Preparation Example 4, the title compound wasobtained as pale yellow acicular crystals from2-chloromethyl-N-methylbenzimidazole (yield: 58.4%).

Melting point: 183°-185° C. (CHCl₃ -n-hexane)

¹ H-NMR(CDCl₃)δ(ppm): 3.81(3H,s,N--CH₃), 4.61(2H,s,--C₆ H₄ --CH₂ --OH),5.29(2H,s,C₈ H₇ N₂ --CH₂ --), 6.88-6.94(2H,m,--C₆ H₄ --), 7.02(1H,s,--C₆H₄ --), 7.16-7.32(4H,m,Ar-H), 7.69(1H,m,C₈ H₇ N₂ --).

IR(KBr)cm⁻¹ : 2850, 1594, 1482, 1441, 1366, 1259, 1227, 1048, 1029, 750.

PREPARATION EXAMPLE 6

Synthesis of 4-(2-N-methylbenzimidazol-2-ylmethoxy)benzyl alcohol

In a similar manner as in Preparation Example 4, the title compound wasobtained as pale yellow prismatic crystals from2-chloromethyl-N-methylbenzimidazole and 4-hydroxybenzyl alcohol (yield:58.4%).

Melting point: 176°-180° C. (CHCl₃ -MeOH-n-hexane)

¹ H-NMR(CDCl₃)δ(ppm): 3.88(3H,s,N--CH₃), 4.62(2H,s,--C₆ H₄ --CH₂ --OH),5.34(2H,s,C₈ H₇ N₂ --CH₂ --), 7.04(2H,d,J=8.6 Hz,--C₆ H₄ --)7.30(2H,d,J=8.6 Hz,--C₆ H₄ --), 7.23-7.38(3H,m,C₈ H₇ N₂ --),7.78(1H,m,C₈ H₇ N₂ --).

IR(KBr)cm⁻¹ : 3174, 2846, 1607, 1585, 1507, 1484, 1240, 1047, 1030, 743.

PREPARATION EXAMPLE 7

Synthesis of 3-(2-benzothiazolylmethoxy)benzyl alcohol

In a similar manner as in Preparation Example 4, the title compound wasobtained as pale yellow acicular crystals from2-chloromethylbenzothiazole (yield: 88.5%).

Melting point: 106°-108° C. (CHCl₃ -n-hexane)

¹ H-NMR(CDCl₃)δ(ppm): 1.86(1H,brt,OH), 4.69(2H,d,J=5.6 Hz,--C₆ H₄ --CH₂--OH), 5.48(2H,s,C₇ H₄ NS--CH₂ --), 6.93-7.03(2H,m,Ar-H),7.08(1H,br,Ar-H), 7.29(1H,dd,J=8.1,8.1 Hz,Ar-H),7.40(1H,ddd,J=7.6,7.1,1.2 Hz,Ar-H), 7.50(1H,ddd,J=7.6,7.1,1.2 Hz,Ar-H),7.90(1H,d,J=7.6 Hz,Ar-H), 8.03(1H,d,J=7.6 Hz,Ar-H).

IR(KBr)cm⁻¹ : 3322, 1596, 1439, 1365, 1264, 1207, 1156, 1062, 752.

PREPARATION EXAMPLE 8

Synthesis of 4-(2-benzothiazolylmethoxy)benzyl alcohol

In a similar manner as in Preparation Example 4, the title compound wasobtained as colorless acicular crystals from 2-chloromethylbenzothiazoleand 4-hydroxybenzylalcohol (yield: 89.8%).

Melting point: 137°-139° C. (CHCl₃ -n-hexane)

¹ H-NMR(CDCl₃)δ(ppm): 1.86(1H,overlapped with H₂ O,OH), 4.63(2H,d,J=5.9Hz,--C₆ H₄ --CH₂ --OH), 5.50(2H,s,C₇ H₄ NS--CH₂ --),7.03(2H,dd,J=8.5,2.0 Hz,Ar-H), 7.32(2H,dd,J=8.5,2.0 Hz,Ar-H),7.40(1H,ddd,J=8.1,8.1,1.2 Hz,Ar-H), 7.50(1H,ddd,J=8.1,8.1,1.2 Hz,AR-H),7.89(1H,dd,J=8.1,1.2 Hz,Ar-H), 8.03(1H,dd,J=8.1,1.2 Hz,Ar-H).

IR(KBr)cm⁻¹ : 3364, 1612, 1585, 1522, 1512, 1361, 1252, 1056, 755.

PREPARATION EXAMPLE 9

Synthesis of 3- N-(2-ethoxyethyl)benzimidazol-2-ylmethoxy!benzyl alcohol

In a similar manner as in Preparation Example 4, the title compound wasobtained as colorless acicular crystals from2-chloromethyl-N-(2-ethoxyethyl)benzimidazole (yield: 90.3%).

Melting point: 105°-107° C. (CHCl₃ -n-hexane)

¹ H-NMR(CDCl₃)δ(ppm): 1.10(3H,t,J=6.8 Hz,CH₂ CH₂ OCH₂ CH₃),2.24(1H,br,--C₆ H₄ --CH₂ OH), 3.39(2H,q,J=6.8 Hz,CH₂ CH₂ OCH₂ CH₃),3.74(2H,t,J=5.4 Hz,--CH₂ CH₂ OCH₂ CH₃), 4.48(2H,t,J=5.4 Hz,--CH₂ CH₂OCH₂ CH₃), 4.68(2H,d,J=5.6 Hz,--C₆ H₄ --CH₂ --OH), 5.43(2H,s,C₁₁ H₁₃ N₂--CH₂ O--), 6.96-7.62 (2H,m,--C₆ H₄ --), 7.11(1H,s,--C₆ H₄ --),7.23-7.34 (3H,m,Ar-H), 7.41(1H,m,Ar-H), 7.71(1H,m,Ar-H).

IR(KBr)cm⁻¹ : 2875, 1594, 1471, 1445, 1426, 1369, 1258, 1154, 1050,1035, 761.

PREPARATION EXAMPLE 10

Synthesis of 4- N-(2-ethoxyethylbenzimidazol-2-ylmethoxy!benzyl alcohol

In a similar manner as in Preparation Example 4, the title compound wasobtained as pale yellow prismatic crystals from2-chloromethyl-N-(ethoxyethyl)benzimidazole and 4-hydroxybenzyl alcohol(yield: 83.4%).

Melting point: 90°-92° C. (CHCl₃ -n-hexane)

¹ H-NMR(CDCl₃)δ(ppm): 1.10(3H,t, J=7.1 Hz,CH₂ CH₂ OCH₂ CH₃),1.66(1H,t,J=5.7 Hz,--C₆ H₄ --CH₂ OH), 3.39(2H,q,J=7.1 Hz,CH₂ CH₂ OCH₂CH₃), 3.75(2H,t,J=5.6 Hz,--CH₂ CH₂ OCH₂ CH₃), 4.49(2H,t,J=5.6 Hz,--CH₂--CH₂ OCH₂ CH₃), 4.62(2H,d,J=5.7 Hz,--C₆ H₄ --CH₂ --OH), 5.44(2H,s,C₁₁H₁₃ N₂ --CH₂ O--), 7.08(2H,d,J=8.8 Hz,--C₆ H₄ --), 7.25-7.34(4H,m,Ar-H),7.41(1H,m,Ar-H), 7.78(1H,m,Ar-H).

IR(KBr)cm⁻¹ : 3180, 2858, 1609, 1587, 1509, 1472, 1417, 1237, 1117,1036, 747.

EXAMPLES 36-46

Using the alcohol compounds obtained in Preparation Examples 5-10, thefollowing compounds were obtained in a similar manner as in Example 33.

                  TABLE 3                                                         ______________________________________                                        Ex.   Compound (1)         mp(°C.)                                     ______________________________________                                        36    7- 3-(N-methylbenzimidazol-2-yl                                                                    208-210                                                  methoxy)benzyloxy!-3,4-dihydro-2H-                                                                 (dec)                                                    1,4-benzothiazin-3-one                                                  37    4- 3-(N-methylbenzimidazol-2-yl                                                                    229-231                                                  methoxy)benzyloxy!-3,3,7-trimethyl-                                           2,3-hydro-1H-indol-2-one                                                38    7- 4-(N-methylbenzimidazol-2-yl                                                                    203-207                                                  methoxy)benzyloxy!-3,4-dihydro-2H-                                                                 (dec)                                                    1,4-benzothiazin-3-one                                                  39    4- 4-(N-methylbenzimidazol-2-yl                                                                    207-211                                                  methoxy)benzyloxy!-3,3,7-trimethyl-                                                                (dec)                                                    2,3-hydro-1H-indol-2-one                                                40    7- 3-(2-benzothiazolylmethoxy)-                                                                    185-187                                                  benzyloxy!-3,4-dihydro-2H-1,4-benzo-                                                               (dec)                                                    thiazin-3-one                                                           41    7- 3-(2-benzothiazolylmethoxy)-                                                                    180-181                                                  benzyloxy!-1,2,3,4-tetrahydro-                                                quinol in-2-one                                                         42    7- 4-(2-benzothiazolylmethoxy)-                                                                    199-201                                                  benzyloxy!-1,2,3,4-tetrahydro-                                                quinolin-2-one                                                          43    4- 3-(N-ethoxyethylbenzimidazol-2-                                                                 155-157                                                  yl-methoxy)benzyloxy!-3,3,7-                                                  trimethyl-2,3-dihydro-1H-indol-2-one                                    44    7- 3-(N-ethoxylethylbenzimidazol-2-                                                                122-125                                                  yl-methoxy)benzyloxy!-3,4-dihydro-2H-                                         1,4-benzothiazin-3-one                                                  45    4-  4-(N-ethoxylethylbenzimidazol-2                                                                201-203                                                  yl-methoxy)benzyloxy!-3,3,7-                                                  trimethyl-2,3-dihydro-1H-indol-2-one                                    46    7- 4-(N-ethoxyethylbenzimidazol-2-yl-                                                              170-173                                                  methoxy)benzyloxy!-3,4-dihydro-2H-                                                                 (dec)                                                    1,4-benzothiazin-3-one                                                  ______________________________________                                    

EXAMPLE 47

Synthesis of 8-methyl-5-3-(2-quinolinylmethoxy)benzyloxy!-3-(5-tetrazolyl)-1,2-dihydroquinolin-2-one

A liquid mixture of 0.822 g (1.84 mmol) of the 3-cyano-8-methyl-5-3-(2-quinolinylmethoxy)benzyloxy!-1,2-dihydroquinolin-2-one obtained inExample 3, 0.359 g (5.52 mmol) of NaN₃, 0.295 g (5.52 mmol) of NH₄ Cland 20 ml of DMF was stirred at a bath temperature of 120° C. for 8hours. The solvent was distilled off and the residue was dissolved in alarge amount of a CHCl₃ --MeOH mixed solvent. The solution was washedwith water and then dried over MgSO₄. The solvent was distilled off,whereby 0.519 g of the title compound was obtained as pale yellow powder(yield: 57.5%).

Melting point: 247°-248° C. (decomposed)

¹ H-NMR(DMSO-d₆)δ(ppm): 2.39(3H,s,C8-CH₃), 5.27(2H,s,C₉ H₆ N--CH₂ O),5.39(2H,s,C₉ H₆ N--CH₂ O), 6.80(1H,d,J=8.3 Hz,Ar-H),7.04-7.16(2H,m,Ar-H), 7.22(1H,brs,Ar-H), 7.31-7.40(2H,m,Ar-H),7.55-7.78(3H,m,Ar-H), 7.90-8.00(2H,m,Ar-H), 8.36(1H,d,J=8.3 Hz,Ar-H),9.05(1H,s,C4-H).

IR(KBr)cm⁻¹ : 3056, 1655, 1611, 1492, 1298, 1240, 1103, 815.

EXAMPLE 48

Synthesis of 8-methyl-5-4-(2-quinolinylmethoxy)benzyloxy!-3-(5-tetrazolyl)-1,2-dihydroquinolin-2-one

Using the 3-cyano-8-methyl-5-4-(2-quinolinylmethoxy)benzyloxy!-1,2-dihydroquinolin-2-one obtained inExample 19, the title compound was obtained as pale yellow powder in asimilar manner as in Example 47 (yield: 26.4%).

Melting point: >300° C. (CHCl₃ -n-hexane)

¹ H-NMR(DMSO-d₆)δ(ppm): 5.26(2H,s,C₆ H₄ --CH₂ O), 5.41(2H,s,C₉ H₆ N--CH₂O), 6.85-6.94(1H,br.Ar-H), 7.14(1H,d,J=8.5 Hz,Ar-H),7.20-7.35(1H,m,Ar-H), 7.48(2H,m,Ar-H), 7.54-7.65(2H,m,Ar-H),7.70(1H,d,J=8.5 Hz,Ar-H), 7.73-7.90(1H,m,Ar-H), 8.02(2H,t,J=8.8Hz,Ar-H), 8.42(1H,d,Ar-H), 9.20(1H,brs,CONH).

IR(KBr)cm⁻¹ : 3403, 1659(CONH), 1612, 1519, 1240, 1092, 823.

EXAMPLE 49

Synthesis of 4-3-(2-quinolinylmethoxy)benzyloxy!-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-thione

To 1.189 g (2.71 mmol) of the 4-3-(2-quinolinylmethoxy)benzyloxy!-3,3,7-trimethyl-2,3-dihydro-1H-indol-2-oneobtained in Example 13, 1.076 g (2.71 mmol) of the Lawesson's reagentand 10 ml of toluene were added, followed by stirring at a bathtemperature of 100° C. for 3 hours. After CHCl₃ was added to dissolvethe insoluble matter, the resulting solution was subjected tochromatography on a silica gel column. Subsequent to elution with CHCl₃,recrystallization was conducted from AcOEt, whereby 678 mg of the titlecompound were obtained as pale yellow powder (yield: 55.0%).

Melting point: 174°-176° C. (decomposed)

¹ H-NMR(DMSO-d₆)δ(ppm): 1.51(6H,s,C3-CH₃ ×2), 2.27(3H,s,C7--CH₃),5.07(2H,s,C₆ H₄ -CH₂ O--), 5.41(2H,s,C₉ H₆ N--CH₂ O), 6.57(1H,d,J=8.3Hz,C5-H), 6.82-7.12(5H,m,Ar-H), 7.22-7.38(1H,m,Ar-H),7.48-7.90(5H,m,Ar-H), 8.10(1H,d,J=8.3 Hz,Ar-H), 8.19(1H,d,J=8.8Hz,Ar-H), 10.03(1H,s,CSNH).

IR(KBr)cm⁻¹ : 3122, 3069, 2973, 2906, 1605, 1586, 1509, 1478, 1451,1441, 1370, 1288, 1267, 1178, 1152, 1083, 1065, 819, 788, 781, 738, 688.

EXAMPLE 50

Synthesis of 2-oxo-6-3-(2-quinolinylmethoxy)benzyloxy!-1,2-dihydroquinoline-3-carboxylic acid

To a solution of 255 mg (0.588 mmol) of the 3-cyano-6-3-(2-qinolinylmethoxy)benzyloxy!-1,2-dihydroquinolin-2-one in 10 ml ofEtOH, 10 ml of a 50% aqueous NaOH solution were added, followed bystirring at room temperature for 6 hours. Water was added to thereaction mixture. After the thus-obtained mixture was acidified withconcentrated HCl, the precipitate was collected by filtration.Subsequent to washing with water, the precipitate was dried in air andthen recrystallized from a CHCl₃ --MeOH-ethyl ether mixed solvent,whereby 120 mg of the title compound were obtained as yellow powder(yield: 45.1%).

Melting point: 282°-285° C. (decomposed)

¹ H-NMR(CD₃ OD)δ(ppm): 5.64(2H,s,--C₆ H₄ --CH₂ --), 5.68(2H,s,C₉ H₆N--CH₂ --), 6.87(1H,s,Ar-H), 7.00-7.45(6H,m,Ar-H), 8.03(1H,d,J=8.0Hz,Ar-H), 8.10-8.29(3H,m,Ar-H), 9.01(1H,d,J=8.5 Hz,Ar-H).

IR(KBr)cm⁻¹ : 3421, 1644, 1584, 1450, 1396, 1244, 1154, 821.

EXAMPLE 51

Synthesis of 8-methyl-2-oxo-5-3-(2-quinolinylmethoxy)benzyloxy!-1,2-dihydroquinoline-3-carboxylic acid

Using 3-cyano-8-methyl-5-3-(2-quinolinylmethoxy)benzyloxy!-1,2-dihydroquinolin-2-one obtained inExample 3, the title compound was obtained as pale yellow powder in asimilar manner as in Example 5 (yield: 78.3%).

Melting point: 237°-239° C. (CHCl₃ --MeOH)

¹ H-NMR(DMSO-d₆)δ(ppm): 2.39(3H,s,C8-CH₃), 5.26(2H,s,--C₆ H₄ --CH₂ O),5.39(2H,s,C₉ H₆ N--CH₂ O), 6.87(1H,d,J=8.8 Hz,C7-H),7.03-7.16(2H,m,Ar-H), 7.19(1H,s,C₆ H₄), 7.36(1H,t,J=8.0 Hz,C₆ H₄),7.47(1H,d,J=8.8 Hz,Ar-H), 7.57-7.67(2H,m,Ar-H), 7.70-7.80(1H,m,Ar-H),7.97(2H,d,J=8.0 Hz,C₆ H₄), 8.36(1H,d,J=8.8 Hz,C6-H), 8.98(1H,s,C₄ --H),12.25(1H,brs,CONH), 14.71(1H,brs,COOH).

IR(KBr)cm⁻¹ : 2800-2300(COOH), 1742(COOH), 1621(CONH), 1497, 1438, 1276,1261, 1087.

EXAMPLE 52

Synthesis of 8-methyl-2-oxo-5-4-(2-quinolinylmethoxy)benzyloxy!-1,2-dihydroquinoline-3-carboxylic acid

Using 3-cyano-8-methyl-5-4-(2-quinolinylmethoxy)benzyloxy!-1,2-dihydroquinolin-2-one obtained inExample 19, the title compound was obtained as pale yellow powder in asimilar manner as in Example 50 (yield: 62.9%).

Melting point: 260°-261° C. (decomposed)

¹ H-NMR(DMSO-d₆)δ(ppm) : 2.41(3H,s,C8-CH₃), 5.20(2H,s,C₆ H₄ --CH₂ O),5.40(2H,s,C₉ H₆ N--CH₂ O), 6.97(1H,d,J=8.3 Hz,Ar-H), 7.13(2H,d,J=8.8Hz,Ar-H), 7.42-7.84(6H,m,Ar-H), 7.95-8.08(2H,m,Ar-H), 8.43(1H,d,J=8.3Hz,Ar-H), 8.96(1H,s,C4-H), 12.30(1H,brs,CONH), 14.70(1H,brs,COOH).

IR(KBr)cm⁻¹ : 2800-2300(COOH), 1753(COOH), 1624(CONH), 1495, 1433, 1252,1240, 1082, 870, 830, 805.

EXAMPLE 53

Synthesis of 3-cyano-8-methyl-5-3-(2-quinolinylmethoxy)benzoyloxy!-1,2-dihydroquinolin-2-one

A liquid mixture of 0.838 g (3 mmol) of 3-(2-quinolinylmethoxy)benzoicacid, 0.601 g (3 mmol) of 3-cyano-5-hydroxy-8-methylcarbostyryl, 50 mlof DMF, 0.931 g (6 mmol) of WSC.HCl and 0.73 g (0.6 mmol) of4-dimethylaminopyridine was stirred under an argon gas stream at a bathtemperature of 50° C. for 2 days. The solvent was distilled off from thereaction mixture under reduced pressure. Water was added to the residue,and the resulting mixture was extracted with a 2:1 mixed solvent ofCHCl₃ and MeOH. The extract was washed with water, dried over MgSO₄ andthen concentrated. The concentrate was allowed to stand overnight,whereby 0.495 g of the title compound was obtained as yellow powder(yield: 35.8%).

Melting point: 257°-260° C. (decomposed)

¹ H-NMR(DMSO-d₆)δ(ppm): 2.46(3H,s,CH₃), 5.51(2H,s,CH₂ O--C₆ H₄),7.14(1H,d,J=7.8 Hz,Ar-H), 7.42-7.91(8H,m,Ar-H), 8.01(2H,d,J=8.8Hz,Ar-H), 8.44(1H,d,J=8.3 Hz,AR-H), 8.83(1H,s,C4-H), 11.80(1H,brs,CONH).

IR(KBr)cm⁻¹ : 3174, 3047, 2230(CN), 1754(COO), 1660(CONH), 1618, 1585,1491, 1278, 1238, 1200, 1074, 1043, 740.

EXAMPLES 54-69

The following compounds were obtained in a similar manner as in Example53.

                  TABLE 4                                                         ______________________________________                                        Ex.   Compound (1)         mp(°C.)                                     ______________________________________                                        54    8-Methyl-5- 3-(2-quinolinylmethoxy)-                                                               162-164                                                  benzoyloxy!-1,2,3,4-tetrahydro-                                               quinol in-2-one                                                         55    6- 3-(2-Quinolinylmethoxy)benzoyl-                                                                 215-217                                                  oxy!-1,2,3,4-tetrahydroquinolin-2-one                                   56    7- 3-(2-Quinolinylmethoxy)benzoyl-                                                                 177-179                                                  oxy!-1,2,3,4-tetrahydroquinolin-2-one                                   57    7- 3-(2-Quinolinylmethoxy)benzoyloxy-                                                              175-177                                                  2,3,4,5-tetrahydro-1H-benzo b!azepin-                                         2-one                                                                   58    7- 3-(2-Quinolinylmethoxy)benzoyl-                                                                 217-219                                                  oxy!-3,4-dihydro-2H-1,4-benzothiazin-                                                              (dec)                                                    3-one                                                                   59    3,3-Dimethyl-5- 3-(2-quinolinyl-                                                                   224-226                                                  methoxy)benzoyloxy!-2,3-dihydro-1H-                                                                (dec)                                                    indol-2-one                                                             60    3,3-Dimethyl-6- 3-(2-quinolinyl-                                                                   180-184                                                  methoxy)benzoyloxy!-2,3-dihydro-1H-                                                                (dec)                                                    indol-2-one                                                             61    3,3-Dimethyl-7- 3-(2-quinolinyl-                                                                   221-224                                                  methoxy)benzoyloxy!-2,3-dihydro-1H-                                                                (dec)                                                    indol-2-one                                                             62    3-Cyano-8-methyl-5- 4-(2-quinolinyl-                                                               277-278                                                  methoxy)benzoyloxy!-1,2-dihydro-                                                                   (dec)                                                    quinolin-2-one                                                          63    8-Methyl-5-  4-(2-quinolinylmethoxy)-                                                              200-202                                                  benzoyloxy!-1,2,3,4-tetrahydro-                                               quinolin-2-one                                                          64    6- 4-(2-Quinolinylmethoxy)benzoyl-                                                                 248-250                                                  oxy!-1,2,3,4-tetrahydroquinolin-2-one                                                              (dec)                                              65    7- 4-(2-Quinolinylmethoxy)benzoyl-                                                                 244-246                                                  oxy!-1,2,3,4-tetrahydroquinolin-2-one                                                              (dec)                                              66    7- 4-(2-Quinolinylmethoxy)benzoyl-                                                                 240-243                                                  oxy!-3,4-dihydro-2H-1,4-benzothiazin-                                                              (dec)                                                    3-one                                                                   67    3,3-Dimethyl-5- 4-(2-quinolinyl-                                                                   227-230                                                  methoxy)benzoyloxy!-2,3-dihydro-1H-                                                                (dec)                                                    indol-2-one                                                             68    3,3-Dimethyl-6- 4-(2-quinolinyl-                                                                   211-215                                                  methoxy)benzoyloxy!-2,3-dihydro-1H-                                                                (dec)                                                    indol-2-one                                                             69    3,3-Dimethyl-7- 4-(2-quinolinyl-                                                                   193-196                                                  methoxy)benzoyloxy!-2,3-dihydro-1H-                                                                (dec)                                                    indol-2-one                                                             ______________________________________                                    

EXAMPLES 70-73

Using 8-amino-3,4-dihydro-2H-1,4-benzothiazin-3-one or7-amino-3,4-dihydro-2H-1,4-benzothiazin-3-one, the following compoundswere obtained in a similar manner as in Example 53.

                  TABLE 5                                                         ______________________________________                                        Ex.    Compound (1)        mp(°C.)                                     ______________________________________                                        70     8- 3-(2-Quinolinylmethoxy)benzoyl-                                                                235-238                                                   amino!-3,4-dihydro-2H-1,4-benzo-                                                                  (dec)                                                     thiazin-3-one                                                          71     8- 4-(2-Quinolinylmethoxy)benzoyl-                                                                277-279                                                   amino!-3,4-dihydro-2H-1,4-benzo-                                                                  (dec)                                                     thiazin-3-one                                                          72     7- 3-(2-Quinolinylmethoxy)benzoyl-                                                                240-242                                                   amino!-3,4-dihydro-2H-1,4-benzo-                                                                  (dec)                                                     thiazin-3-one                                                          73     7- 4-(2-Quinolinylmethoxy)benzoyl-                                                                258-260                                                   amino!-3,4-dihydro-2H-1,4-benzo-                                                                  (dec)                                                     thiazin-3-one                                                          ______________________________________                                    

EXAMPLE 74

Synthesis of 7-3-(2-quinolinylmethoxy)benzyloxy!-3,4-dihydro-2H-1,4-benzothiazin-3-one1,1-dioxide

7-3-(2-Quinolinylmethoxy)benzyloxy!-3,4-dihydro-2H-1,4-benzothiazin-3-one(0.639 g, 1.49 mmol) obtained in Example 10 was dissolved in 90 ml ofCHCl₃, to which a solution of 1.04 g (3 mmol) of m--CPBA(metachloroperbenzoic acid) in 30 ml of CHCl₃ was added at roomtemperature. The resultant mixture was stirred for 72 hours. Thereaction mixture was washed successively with a saturated aqueoussolution of NaHCO₃ and water in this order, dried over magnesium sulfateand then concentrated, whereby 0.219 g of the title compound wasobtained as pale yellow powder (yield: 31.9%).

Melting point: 233°-234° C. (decomposed)

¹ H-NMR(DMSO-d₆)δ(ppm): 4.68(2H,s,CH₂ at C2), 5.19(2H,s,C₆ H₄ --CH₂O--), 5.49(2H,s,C₉ H₆ N--CH₂ --), 7.00-7.42(6H,m,Ar-H),7.58-7.92(4H,m,Ar-H), 8.02(1H,d,J=8.8 Hz,Ar-H), 8.13(1H,d,J=8.8Hz,Ar-H), 8.61(1H,d,J=8.8 Hz,Ar-H), 11.08(1H,s,CONH).

IR(KBr)cm⁻¹ : 1702(CONH), 1494, 1326, 1309(SO₂), 1253, 1237, 1223,1138(SO₂).

EXAMPLES 75-80

Using the compounds obtained in Examples 11, 32, 33, 36, 40 an 72, thefollowing compounds were obtained similar manner as in Example 74.

                  TABLE 6                                                         ______________________________________                                        Ex.     Compound (1)         mp (°C.)                                  ______________________________________                                        75      7- 3-(7-Chloro-2-quinolinylmethoxy)-                                                               229-231                                                  benzyloxy!-3,4-dihydro-2H-1,4-benzo-                                                               (dec)                                                    thiazin-2-one 1,1-dioxide                                             76      8- 3-(2-Quinolinylmethoxy)benzyloxy!-                                                              221-223                                                  2,3,4,5-tetrahydro-1,5-benzo-                                                                      (dec)                                                    thiazepin-4-one 1,1-dioxide                                           77      7- 3-(2-Quinolinylmethoxy)benzyloxy!-                                                              227-229                                                  3,4-dihydro-2H-1,4-benzothiazin-3-                                                                 (dec)                                                    one 1,1-dioxide                                                       78      7- 3-(2-Benzothiazolylmethoxy)benzyl-                                                              198-200                                                  oxy!-3,4-dihydro-2H-1,4-benzothiazin-                                                              (dec)                                                    3-one 1,1-dioxide                                                     79      7- 3-(N-Methylbenzimidazol-2-yl-                                                                   144-149                                                  methoxy)benzyloxy!-3,4-dihydro-2H-                                            1,4-benzothiazin-3-one 1,1-dioxide                                    80      7- 3-(2-Quinolinylmethoxy)benzoyl-                                                                 244-250                                                  amino-3,4-dihydro-2H-1,4-benzo-                                                                    (dec)                                                    thiazin-3-one 1,1-dioxide                                             ______________________________________                                    

EXAMPLE 81

Synthesis of trans-7- 3-2-(7-chloroquinolin-2-yl)ethenyl!benzyloxy!-2H-3,4-dihydro-1,4-benzothiazin-3-one

1) Synthesis of 7-chloro-2-quinolylmethyl(triphenyl)phosphilic chloride

7-Chloro-2-chloromethylquinoline (4.81 g, 22.7 mmol) was dissolved in100 ml of toluene, followed by the addition of 7.74 g (22.7 mmol) oftriphenylphosphine. The resultant mixture was heated under reflux for 24hours. After the reaction mixture was concentrated, insoluble matter wascollected by filtration and then washed with ethyl ether, whereby 8.54 gof the title compound were obtained as gray powder (yield: 79.3%).

¹ H-NMR(CDCl₃)δ(ppm): 6.09(2H,d,J=14.4 Hz,--CH₂ P--),7.43(1H,dd,J=8.6,2.0 Hz,Ar-H), 7.49(1H,d,J=2.0 Hz,Ar-H),7.54-7.79(10H,m,Ar-H), 7.86-7.98(6H,m,Ar-H), 8.05(1H,d,J=8.6 Hz,Ar-H),8.25(1H,d,J=8.5 Hz,Ar-H).

2) Synthesis of 3- 2-{2-(7-chloro)quinolyl}!ethenylbenzaldehyde

7-Chloro-2-quinolylmethyl(triphenyl)phosphilic chloride (4.60 g, 9.70mmol) was dissolved in 100 ml of dry THF, to which a solution of 1.09 g(9.70 mmol) of t-BuOK in 50 ml of dry THF was added dropwise under an N₂gas stream. The resultant mixture was stirred at room temperature for 10minutes. To the solution, a solution of 1.30 g (9.70 mmol) ofisophthalaldehyde in 30 ml of dry THF was added dropwise. The resultantmixture was stirred at room temperature for 2 hours. Water (300 ml) wasadded to the reaction mixture, followed by the extraction of the organiclayer with CHCl₃. The extract was dried over anhydrous Na₂ SO₄, thesolvent was distilled off and the residue was then recrystallized from aCHCl₃ -MeOH-n-hexane mixed solvent, whereby 4.46 g of the title compoundwere obtained as pale yellow powder (a 6:94 mixture of the cis-form andthe trans-form) (yield: 91.9%).

Melting point: 105°-107° C.

¹ H-NMR(CDCl₃)δ(ppm): 7.40-7.92(9H,m,Ar-H) , 8.07-8.18(2H,m,Ar-H),10.08(1H(94%),s,CHO(trans)), 10.13(1H,(6%),s,CHO(cis)).

IR(KBr)cm⁻¹ : 1688, 1591, 1439, 1190, 1122, 973, 721, 542.

3) Synthesis of trans-3- 2-(7-chloro)quinolin-2-yl)ethenyl!benzylalcohol

3- 2-(7-Chloroquinolin-2-yl)ethenyl!benzaldehyde (cis/trans=6:94) (2.53g, 7.28 mmol) was suspended in 160 ml of MeOH, followed by the additionof 182 mg (10.4 mmol) of NaBH₄. The resultant mixture was then stirredat room temperature for 24 hours. Insoluble matter was filtered off fromthe reaction mixture and then washed with CHCl₃. The filtrate and thewashing were combined together, from which the solvent was distilled offunder reduced pressure. The residue was subjected to chromatography on asilica gel column. Subsequent to elution with CHCl₃, recrystallizationwas conducted from a CHCl₃ -n-hexane mixed solvent, whereby 1.25 g ofthe title compound were obtained as pale yellow leaflet crystals (yield:58.1%).

Melting point: 138°-140° C.

¹ H-NMR(CDCl₃)δ(ppm): 7.31-7.48(4H,m,Ar-H and vinyl-H), 7.56(1H,d,J=7.6Hz,Ar-H), 7.63(1H,d,J=8.5 Hz,Ar-H), 7.65(1H,s,Ar-H), 7.71(1H,d,J=8.8Hz,Ar-H), 7.71(1H,d,J=13.7 Hz,vinyl-H), 8.05-8.13(2H,m,Ar-H).

IR(KBr)cm⁻¹ : 1607, 1591, 1497, 1409, 1040, 974, 840, 697.

4) Synthesis of trans-3-2-(7-chloroquinolin-2-yl)ethenyl!benzyloxy!-3,4-dihydro-2H-1,4-benzothiazin-3-one

To a solution of 813 mg (2.75 mmol) of trans-3-2-(7-chloroquinolin-2-yl)ethenyl!benzyl alcohol in 40 ml of CHCl₃, 1.0ml of SOCl₂ was added, followed by stirring at room temperature for 24hours. A small amount of MeOH was added to the reaction mixture and thesolvent was distilled off under reduced pressure, whereby trans-3-2-(7-chloroquinolin-2-yl)ethenyl!-benzyl chloride was obtained as paleyellow powder.

It was added to a solution of 415 mg (2.29 mmol) of7-hydroxy-3,4-dihydro-2H-(1,4)-benzothiazin-3-one in 70 ml of DMF,followed by the addition of 475 mg (3.44 mmol) of K₂ CO₃ and 31.8 mg(0.23 mmol) of tetra-n-butylammonium bromide. The resultant mixture wasstirred under an argon gas stream at 100° C. for 16 hours. The reactionmixture was concentrated under reduced pressure, and CHCl₃ and waterwere added to the residue to extract the reaction product into theorganic layer. The extract was dried over Na₂ SO₄ and then concentratedunder reduced pressure. The residue was subjected to chromatography on asilica gel column. Subsequent to elution with CHCl₃, recrystallizationwas conducted from a CHCl₃ -n-hexane mixed solvent, whereby 193 mg ofthe title compound were obtained as pale yellow powder (yield: 18.4%).

Melting point: 205°-208° C. (decomposed)

¹ H-NMR(CDCl₃)δ(ppm): 3.42(2H,s,--SCH₂ CONH--), 5.07(2H,s,--C₆ H₄ --CH₂--), 6.78(1H,d,J=8.8 Hz,C5-H), 6.83(1H,dd,J=8.8,2.7 Hz,C6-H),6.97(1H,d,J=2.7 Hz,C8-H), 7.35-7.48(4H,m,Ar-H and vinyl-H),7.59-7.78(5H,m,Ar-H and vinyl-H), 8.02(1H,br,NH), 8.02-8.13(2H,m,Ar-H).

IR(KBr)cm⁻¹ : 1668, 1608, 1592, 1497, 1377, 1223, 1068, 834, 692.

EXAMPLE 82

Synthesis of 7-3-(2-quinazolinylmethoxy)benzyloxy!-2,3,4,5-tetrahydro-1H-benzb!azepin-2-one

The title compound was obtained in a similar manner as in Example 33(yield: 15.3%).

Melting point: 128°-131° C.

EXAMPLE 83

Synthesis of 7-3-(1-methylbenzimidazol-2-yl)-benzyloxy!-2,3,4,5-tetrahydro-1H-benzb!azepin-2-one

Using the alcohol compound obtained in Preparation Example 5, the titlecompound was obtained in a similar manner as in Example 33 (yield:23.3%).

Melting point: 159°-162° C.

EXAMPLE 84

Synthesis of 7-3-(2-quinolinylmethoxy)benzyloxy!-2,3,4,5-tetrahydro-1H-benzc!azepin-1-one

The title compound was obtained in a similar manner as in Example 1(yield: 79.3%).

Melting point: 172°-173° C.

EXAMPLE 85

Synthesis of 7-4-(2-quinolinylmethoxy)-benzyloxy!-2,3,4,5-tetrahydro-1H-benzc!azepin-1-one

The title compound was obtained in a similar manner as in Example 18(yield: 63.7%).

Melting point: 181°-183° C.

EXAMPLE 86

Synthesis of 7-3-(2-quinazolinylmethoxy)benzyloxy!-2,3,4,5-tetrahydro-1H-benzc!azepin-1-one

The title compound was obtained in a similar manner as in Example 33(yield: 28.4%).

Melting point: 172°-173° C.

EXAMPLE 87

Synthesis of 7-3-(2-quinolinylmethoxy)benzyloxy!-2,3,4,5-tetrahydro-tetrazolo 5,1-a!2!benzazepin

The title compound was obtained in a similar manner as in Example 1(yield: 54.8%).

Melting point: 136°-138° C.

EXAMPLE 88

Synthesis of 7-4-(2-quinolinylmethoxy)benzyloxy!-2,3,4,5-tetrahydro-tetrazolo-5,1-a!2!benzazepin

The title compound was obtained in a similar manner as in Example 18(yield: 17.9%).

Melting point: 217°-219° C.

EXAMPLE 89

Synthesis of 6- 3-(2-quinolinylmethoxy)benzyloxy!-1-tetralone

The title compound was obtained in a similar manner as in Example 1(yield: 36.5%).

Melting point: 93° C.

EXAMPLE 90

Synthesis of 6- 3-(2-quinazolinylmethoxy)benzyloxy!-1-tetralone

The title compound was obtained in a similar manner as in Example 33(yield: 7.4%).

Melting point: 97°-98° C.

EXAMPLE 91

Synthesis of 7-3-(2-quinolinylmethoxy)benzylidenamino!-3,4-dihydro-2H-1,4-benzothiazin-3-one

A liquid mixture of 1.316 g (5 mmol) of3-(2-quinolinylmethoxy)benzaldehyde, 0.901 g (5 mmol) of7-amino-3,4-dihydro-2H-1,4-benzothiazin-3-one and 70 ml of EtOH washeated under reflux and stirring for 24 hours. The mixture was thenallowed to cool down. The precipitate was collected by filtration,whereby 1.969 g of the title compound were obtained as pale yellowpowder (yield: 92.3%).

Melting point: 209°-210° C. (decomposed)

¹ H-NMR(DMSO-d₆)δ(ppm): 3.50(2H,s,CH₂ at C2), 5.45(2H,s,C₉ H₆ NCH₂ O),7.01(1H,d,J=8.8 Hz,Ar-H), 7.08-7.87(9H,m,Ar-H), 8.02(2H,t,J=8.3Hz,Ar-H), 8.43(1H,d,J=8.3 Hz,Ar-H), 8.63(1H,s,--CH═N--),10.65(1H,s,CONH).

IR(KBr)cm⁻¹ : 3183, 1679, 1624, 1598, 1584, 1492, 1371, 1267, 1255,1202, 826, 816, 783.

EXAMPLE 92

Synthesis of 7-4-(2-quinolinylmethoxy)benzylidenamino!-3,4-dihydro-2H-1,4-benzothiazin-3-one

The title compound was obtained in a similar manner as in Example 91(yield: 96.1%).

Melting point: 277°-279° C. (decomposed)

EXAMPLE 93

Synthesis of 8-3-(2-quinolinylmethoxy)benzylidenamino!-3,4-dihydro-2H-1,4-benzothiazin-3-one

The title compound was obtained in a similar manner as in Example 91(yield: 93.3%).

Melting point: 170°-173° C. (decomposed)

EXAMPLE 94

Synthesis of 7-3-(2-quinolinylmethoxy)benzylamino!-3,4-dihydro-2H-1,4-benzothiazin-3-one

7-3-(2-Quinolinylmethoxy)benzylidenamino!-3,4-dihydro-2H-1,4-benzothiazin-3-one(6.383 g, 15 mmol) obtained in Example 91 was dissolved in a mixedsolvent consisting of 200 ml of DMF and 50 ml of MeOH, followed by theaddition of 2.26 g (60 mmol) of NaBH₄ in small portions. After theresultant mixture was stirred for 30 minutes at room temperature, thesolvent was distilled off under reduced pressure. Water was added to theresidue, followed by extraction with CHCl₃. The extract was washed withwater, dried over MgsO₄ and then concentrated. The concentrate wasrecrystallized from MeOH-AcOEt, whereby 5.117 g of the title compoundwere obtained as white powder (yield: 79.8%).

Melting point: 147°-149° C.

¹ H-NMR(DMSO-d₆)δ(ppm): 3.34(2H,s,CH,at C2), 4.20(2H,d,J=5.9 Hz, --CH₂NH--), 5.34(2H,s,C₉ H₆ NCH₂ O), 6.18(1H,t,J=5.9 Hz,NH),6.32-6.50(2H,m,Ar-H), 6.68(1H,d,J=8.8 Hz,Ar-H), 6.82-7.00(2H,m,Ar-H),7.07 (1H,s,Ar-H), 7.24(1H,t,J=7.8 Hz,Ar-H), 7.55-8.07(5H,m,Ar-H),8.40(1H,d,J=8.8 Hz,Ar-H), 10.13(1H,s,CONH).

IR(KBr)cm⁻¹ : 3430, 1663, 1613, 1600, 1505, 1263, 1251, 1157, 823, 792,780.

EXAMPLE 95

Synthesis of 8-3-(2-quinolinylmethoxy)benzylamino!-3,4-dihydro-2H-1,4-benzothiazin-3-one

The title compound was obtained in a similar manner as in Example 94(yield: 81.3%).

Melting point: 179°-181° C.

EXAMPLE 96

Syntheses of 7-N-methyl-N-{3-(2-quinolinylmethoxy)benzyl}amino!-3,4-dihydro-2H-1,4-benzothiazin-3-one(a) and 4-methyl-7-N-methyl-N-{3-(2-quinolinylmethoxy)benzyl}amino!-3,4-dihydro-2H-1,4-benzothiazin-3-one(b)

After a mixture of 2.147 g (5.02 mmol) of 1,4-benzothiazin-3-one, 0.852g (6 mmol) of CH₃ I, 1.658 g (12 mmol) of K₂ CO₃, 0.161 g (0.5 mmol) of(n-Bu)₄ NBr and 60 ml of DMF was stirred at room temperature for 3 days,the solvent was distilled off under reduced pressure. Water was added tothe residue, followed by extraction with CHCl₃. The extract was washedwith water, dried over MgSO₄ and then concentrated. The residue wassubjected to chromatography on a silica gel column. Subsequent toelution with CHCl₃, the first eluate was recrystallized from AcOEt,whereby 0.091 g of the title compound (b) was obtained (yield: 4.0%).Subsequently, the second eluate was recrystallized from CHCl₃ --MeOH,whereby 0.500 g of the title compound (a) was obtained as colorlessfoliaceous crystals (yield: 22.6%).

Title compound (a)

Melting point: 196°-198° C. (decomposed)

¹ H-NMR(CDCl₃)δ(ppm): 2.96(3H,s,CH₃ --N--C7), 3.39(2H,s,CH₂ at C2),4.44(2H,S,--CH₂ N(Me)--), 5.35(2H,s,C₉ H₆ NCH₂ O), 6.47(1H,dd,J=2.8,8.8Hz,C6-H), 6.60(1H,d,J=2.8 Hz,C8-H), 6.61(1H,d,J=8.8 Hz,C5-H),6.77-6.97(3H,m,Ar-H), 7.24(1H,t,J=7.8 Hz,Ar-H), 7.56(1H,t,J=6.8Hz,Ar-H), 7.64(1H,d,J=8.8 Hz,Ar-H), 7.70-7.78(1H,m,Ar-H),7.83(1H,d,J=8.3 Hz,Ar-H), 7.93(1H,br.s,CONH), 8.07(1H,d,J=8.3 Hz,Ar-H),8.18(1H,d,J=8.8 Hz,Ar-H).

IR(KBr)cm⁻¹ : 1666, 1610, 1510, 1373, 1286, 1069, 783.

Title compound (b)

Melting point: 108°-110° C.

¹ H-NMR(CDCl₃)δ(ppM): 2.97(3H,s,CH₃ --N--C7), 3.37(3H,s,N4--CH₃),3.38(2H,s,CH₂ at C2), 4.46(2H,S,--CH₂ N(Me)--), 5.35(2H,s,C₉ H₆ NCH₂ O),6.55(1H,dd,J=2.9,8.8 Hz,C6-H), 6.66(1H,d,J=2.9 Hz,C8-H),6.78-6.95(4H,m,Ar-H), 7.25(1H,t,J=7.8 Hz,Ar-H), 7.52-7.60(1H,m,Ar-H),7.65(1H,d,J=8.8 Hz,Ar-H), 7.69-7.86(2H,m,Ar-H), 8.06(1H,d,J=8.3Hz,Ar-H), 8.18(1H,d,J=8.8 Hz,Ar-H).

IR(KBr)cm⁻¹ : 1652, 1608, 1582, 1509, 1373, 1286, 1253, 1141, 1060, 827,782, 748.

EXAMPLE 97

Synthesis of 4-methyl-8-3-(2-quinolinylmethoxy)benzylamino!-3,4-dihydro-2H-1,4-benzothiazin-3-one

After a mixture of 1.690 g (3.95 m-mol) of 8-3-(2-quinolinylmethoxy)benzylamino!-3,4-dihydro-2H-1,4-benzothiazin-3-oneobtained in Example 95, 0.673 g (4.74 mmol) of CH₃ I, 1.311 g (9.5 mmol)of K₂ CO₃, 0.129 g (0.4 mmol) of (n-Bu)₄ NBr and 50 ml of DMF wasstirred at room temperature for 3 days, the solvent was distilled offunder reduced pressure. Water was added to the residue, followed byextraction with CHCl₃. The extract was washed with water, dried overMgSO₄ and then concentrated. The residue was subjected to chromatographyon a silica gel column. Subsequent to elution with CHCl₃,recrystallization was conducted from an acetone-n-hexane mixed solvent,whereby 1.000 g of the title compound was obtained (yield: 57.3%).

Melting point: 102°-104° C.

¹ H-NMR(CDCl₃)δ(ppm): 3.32(2H,s,CH₂ at C2), 3.41(3H,s,N--CH₃),4.37(2H,d,J=5.4 Hz,C₈ NHCH₂), 4.55(1H,t,J=5.4 Hz,C8-NH), 5.38(2H,s,C₉ H₆NCH₂ O), 6.34(1H,d,J=8.3 Hz,Ar-H), 6.47(1H,d,J=7.8 Hz,Ar-H),6.91-7.08(4H,m,Ar-H), 7.24-7.32(1H,m,Ar-H), 7.51-7.59(1H,m,Ar-H),7.64(1H,d,J=8.3 Hz,Ar-H), 7.70-7.77(1H,m,Ar-H), 7.82(1H,d,J=7.8Hz,Ar-H), 8.06(1H,d,J=9.3 Hz,Ar-H), 8.17(1H,d,J=8.3 Hz,Ar-H).

IR(KBr)cm⁻¹ : 3371, 2965, 1659, 1589, 1470, 1359, 1285, 1252, 1076, 819,768, 742.

Test 1

Antihistaminic Action and Anti-LTD₄ Action (In vitro Tests)

An isolated guinea pig ileum was cut into about 2 cm lengths. Each ileumpiece was suspended in a 20-ml container filled with the Krebs buffer.An isotonic contractive response by histamine or leukotriene D₄ wasrecorded on a recorder. The Krebs buffer was controlled at 37° C.,through which a mixed gas (95%O₂ --5%CO₂) was bubbled. First, histamineor leukotriene D₄ was added to an organ bath to measure itsdose-response. After the ileum piece was washed several times with thebuffer, a test compound (will be identified by its example number; thiswill apply likewise hereinafter) of a predetermined specificconcentration was added. Subsequent to incubation for 30 minutes, thedose-response of histamine or leukotriene D₄ was measured again.Incidentally, in Table 7, the values (%) indicate contraction inhibitionrate at 10⁻⁵ M, while the values in parentheses show pD'₂ values in thecase of antihistaminic action and IC₅₀ values in the case of anti-LTD₄action.

                  TABLE 7                                                         ______________________________________                                        Test      Antihistaminic (%) Anti-LTD.sub.4 action (%)                        comp'd    (10.sup.-5 M)      (10.sup.-5 M)                                    ______________________________________                                         6        37                 98    (4.6 × 10.sup.-7)                    17        100    (pD'.sub.2 5.35)                                                                          96    (1.5 × 10.sup.-6)                    33        65     (pD'.sub.2 5.25)                                                                          100   (1.3 × 10.sup.-7)                    35        16                 87    (1.7 × 10.sup.-6)                    39        100    (pD'.sub.2 6.42)                                                                          98    (4.4 × 10.sup.-7)                    89               (pD'.sub.2 5.09) (2.40 × 10.sup.-7)                     .sup. 96(b)                                                                            98     (pD'.sub.2 6.17) (1.20 × 10.sup.-7)                    ______________________________________                                    

Test 2

Antihistaminic Action and Anti-LTD₄ Action (In vivo Tests)

After the hair on the back of a male Hartley guinea pig was cut off, atest compound was orally administered at 10 mg/kg. One hour later, 5%Evans Blue solution was intravenously administered at 1 ml/kg andimmediately after that, a 0.3 μg/ml solution of histamine and a 0.5μg/ml solution of leukotriene D₄ were intracutaneously administered eachin an amount of 0.1 ml to the back. Thirty minutes later, the guinea pigwas sacrificed under exsanguination, the skin was cut off, and thetransudated color was quantitated by extraction. To a control, 0.5% CMC(carboxylmethylcelluose) was orally administered and the subsequentprocedures were repeated likewise. From the difference in the amount ofthe transudated color between the control and the group administeredwith the test compound, an inhibition rate was calculated.

                  TABLE 8                                                         ______________________________________                                        Test                                                                          comp'd    Anti-H.sub.1 action (%)                                                                    Anti-LTD.sub.4 action (%)                              ______________________________________                                         6        --           12                                                     10        36           32                                                     15        17           37                                                     17        19           21                                                     30        40           44                                                     33        --           40                                                     35        --           11                                                     78        --           32                                                     ______________________________________                                    

Test 3

1) H₁ Receptor Binding Inhibition Test

Incubated at 37° C. for 30 minutes was 1 ml of a 50 mM phosphate buffer(pH 7.5) which contained 0.5 nM ³ H!mepyramin (activity: 22 Ci/mmol),guinea pig cerebromembranous protein and a test compound. An ice-cooledphosphate buffer was added to terminate the reaction, followed byimmediate filtration through a Wattman CF/C filter. The filter waswashed twice with 20 ml aliquots of the ice-cooled buffer. Theradio-activity of the residue was measured by a liquid scintillationcounter. From a measurement value obtained without the addition of thetest compound and measurements values obtained upon addition of the testcompound at various concentrations, the dose-response of the inhibitoryaction of the test compound was measured and the 50% inhibitoryconcentration (IC₅₀) was determined. Using the Cheng-Prusoff formula, adissociation constant was calculated from the IC₅₀. In a binding assay,10⁻⁴ M R(-)dimethindene was used for the measurement of a nonspecificbinding. From the binding assay, it was found that the receptor was ofonly one type and that the maximum binding (Bmax) was 278±24 fmol/mgprotein. Further, the dissociation constant (K_(D)) of ³ H!mepyramin was3.30±0.26×10⁻⁹ M and when analyzed by a Hill plot, its slope was foundto be 1.005.

2) LTD₄ Receptor Binding Inhibition Test

Incubated at 22° C. for 30 minutes was 0.3 ml of a 10 mM piperazineN,N'-bis(2-ethanesulfonate) buffer (pH 7.5) which contained 0.2 nM ³H!leukotriene D₄, guinea pig pulmomembranous protein and a testcompound. An ice-cooled tris hydrochloride/sodium chloride buffer (10mM/100 mM, pH 7.5) was added to terminate the reaction, followed byimmediate filtration through a Wattman CF/C filter. The filter waswashed twice with 20 ml aliquots of the ice-cooled buffer. Theradio-activity of the residue was measured by a liquid scintillationcounter. By similar methods as in the H₁ receptor test, the IC₅₀ of thetest compound was determined and the dissociation constant wascalculated. In a binding assay, 2 μM leukotriene D₄ was used for themeasurement of a nonspecific binding. From the binding assay, it wasfound that the receptor was of only one type and that the maximumbinding (Bmax) was 988 fmol/mg protein. Further, the dissociationconstant (K_(D)) of ³ H!leukotriene D₄ was 2.16×10⁻¹⁰ M and whenanalyzed by a Hill plot, its slope was found to be 0.99. Incidentally,the values in Table 9 indicate dissociation constants K_(D) (mol) orinhibition rates (%) at high concentrations (a: 100 μM, b: 10 μM).

                  TABLE 9                                                         ______________________________________                                        Test                                                                          comp'd      H.sub.1 receptor (%)                                                                     LTD.sub.4 receptor (%)                                 ______________________________________                                         1          --         1.18 × 10.sup.-7 M                                2          --         1.56 × 10.sup.-6 M                                3          44.sup.a   5.23 × 10.sup.-7 M                                4          --          0.sup.a                                                5          57.sup.a   3.16 × 10.sup.-7 M                                6          18.sup.b   8.14 × 10.sup.-8 M                                7          46.sup.a   2.09 × 10.sup.-7 M                                8          1.45 × 10.sup.-4 M                                                                 3.22 × 10.sup.-7 M                                9          4.76 × 10.sup.-5 M                                                                 1.48 × 10.sup.-7 M                               10          50.sup.a   1.25 × 10.sup.-8 M                               11          47.sup.a   2.20 × 10.sup.-8 M                               12          45.sup.    7.03 × 10.sup.-7 M                               13          --         3.03 × 10.sup.-7 M                               14          29.sup.a   2.15 × 10.sup.-7 M                               15          36.sup.a   37.sup.b                                               16          48.sup.a   2.50 × 10.sup.-6 M                               17          40.sup.a   2.02 × 10.sup.-7 M                               18          7.87 × 10.sup.-5 M                                                                 1.10 × 10.sup.-6 M                               19          --          0.sup.a                                               20          --          0.sup.a                                               21          28.sup.a   33.sup.b                                               22          45.sup.a   1.24 × 10.sup.-6 M                               23          41.sup.a   5.00 × 10.sup.-7 M                               24          2.58 × 10.sup.-5 M                                                                 3.01 × 10.sup.-7 M                               25          5.78 × 10.sup.-5 M                                                                 1.29 × 10.sup.-7 M                               26          --         5.46 × 10.sup.-4 M                               27          38.sup.a   1.39 × 10.sup.-7 M                               28          30.sup.a   1.40 × 10.sup.-6 M                               29          34.sup.a   3.10 × 10.sup.-6 M                               30          32.sup.a   2.00 × 10.sup.-7 M                               31          1.98 × 10.sup.-5 M                                                                 3.04 × 10.sup.-7 M                               32          43.sup.a   1.09 × 10.sup.-7 M                               33          46.sup.a   9.70 × 10.sup.-9 M                               34          1.00 × 10.sup.-4 M                                                                 1.96 × 10.sup.-7 M                               35          8.79 × 10.sup.-5 M                                                                 2.09 × 10.sup.-7 M                               36          1.62 × 10.sup.-5 M                                                                 1.35 × 10.sup.-7 M                               37          28.sup.a   2.04 × 10.sup.-7 M                               38          47.sup.a   3.03 × 10.sup.-7 M                               39          3.74 × 10.sup.-5 M                                                                 4.08 × 10.sup.-7 M                               40          43.sup.a   1.39 × 10.sup.-6 M                               41          1.28 × 10.sup.-4 M                                                                 34.sup.b                                               42          8.36 × 10.sup.-5 M                                                                 17.sup.b                                               43          6.06 × 10.sup.-6 M                                                                 5.51 × 10.sup.-6 M                               44          8.67 × 10.sup.-6 M                                                                 6.30 × 10.sup.-6 M                               45          40.sup.a   32.sup.b                                               46          5.95 × 10.sup.-6 M                                                                 6.40 × 10.sup.-6 M                               47          --         3.35 × 10.sup.-7 M                               48          --         3.04 × 10.sup.-7 M                               49          --         4.00 × 10.sup.-5 M                               50          --         1.08 × 10.sup.-6 M                               51          --         1.17 × 10.sup.-5 M                               52          --         3.02 × 10.sup.-7 M                               53          38.sup.a   1.60 × 10.sup.-8 M                               54          41.sup.a   1.29 × 10.sup.-7 M                               55          43.sup.a   3.48 × 10.sup.-7 M                               56          9.30 × 10.sup.-5 M                                                                 12.sup.a                                               57          5.79 × 10.sup.-5 M                                                                 8.51 × 10.sup.-7 M                               58          --          0.sup.a                                               59          37.sup.a   53.sup.a                                               60          38.sup.a   2.23 × 10.sup.-7 M                               61          28.sup.a   27.sup.b                                               62          --         0                                                      63          40.sup.a   3.06 × 10.sup.-8 M                               64          40.sup.a   12.sup.a                                               65          43.sup.a   13.sup.a                                               66          --         28.sup.b                                               67          49.sup.a   52.sup.a                                               68          28.sup.a   4.28 × 10.sup.-7 M                               69          33.sup.a   3.31 × 10.sup.-7 M                               70          37.sup.a   2.08 × 10.sup.-7 M                               71          28.sup.a    0.sup.a                                               72          --         4.62 × 10.sup.-8 M                               73          --         20.sup.b                                               74          --         2.35 × 10.sup.-4 M                               75          36.sup.a   0                                                      76          1.22 × 10.sup.-4 M                                                                  0.sup.a                                               77          30.sup.a   1.29 × 10.sup.-7 M                               78          29.sup.a   1.26 × 10.sup.-5 M                               79          43.sup.a   42.sup.b                                               80          36.sup.a   27.sup.b                                               81          --         1.30 × 10.sup.-8 M                               82           5.sup.b   6.00 × 10.sup.-8 M                               83           0.sup.b   3.10 × 10.sup.-7 M                               84          6.64 × 10.sup.-5 M                                                                 2.60 × 10.sup.-8 M                               85          5.31 × 10.sup.-5 M                                                                 1.15 × 10.sup.-7 M                               86           9.sup.b   9.28 × 10.sup.-8 M                               87          6.72 × 10.sup.-5 M                                                                 1.14 × 10.sup.-8 M                               88          3.11 × 10.sup.-5 M                                                                 30.sup.b                                               89           6.sup.b   4.13 × 10.sup.-8 M                               90           8.sup.b   1.29 × 10.sup.-8 M                               91          1.20 × 10.sup.-7 M                                                                 37.sup.b                                               92          1.20 × 10.sup.-7 M                                                                  0.sup.b                                               93          38.sup.b   1.51 × 10.sup.-6 M                               94          37.sup.b   3.15 × 10.sup.-7 M                               95          33.sup.b   6.08 × 10.sup.-7 M                                .sup. 96(a)                                                                               4.sup.b    9.sup.b                                                .sup. 96(b)                                                                              14.sup.b   3.15 × 10.sup.-7 M                               97           7.sup.b   6.81 × 10.sup.-7 M                               ______________________________________                                    

We claim:
 1. A phenylene derivative represented by the following formula(1) or a salt thereof: ##STR12## wherein R¹ represents a hydrogen atomor a halogen atom,A represents --CH═CH--, --CH═N--, W represents--CH═CH-- or --CH₂ O--, X represents CH₂ O--, --CH₂ S--, ##STR13##--CH═N--, --COO-- or --CONH--, R³ being a hydrogen atom or a lower alkylgroup, Y represents the following formula (a), (b) or (c): ##STR14##wherein R⁴ is a hydrogen atom or a lower alkyl group, B¹ represents##STR15## R⁷ and R⁸ each being a hydrogen atom or a lower alkyl group,R⁹ being a hydrogen atom, a cyano group, a halogen atom, a carboxylgroup or a tetrazolyl group, l and m being a value of from 0 to 2, and nbeing a value of 1 to 2, R⁵ represents a hydrogen atom or a lower alkylgroup, Z¹ represents an oxygen atom or a sulfur atom, B² represents--CH₂ CH₂ -- or --CH₂ CH₂ CH₂ --, R⁶ represents a hydrogen atom or alower alkyl group, Z² represents an oxygen atom or a sulfur atom, or Z²and R⁶ are coupled together with the adjacent nitrogen atom to form atetrazolyl group.
 2. The phenylene derivative or salt thereof accordingto claim 1, wherein in the formula (1), R³, R⁴, R⁵, R⁶, R⁷ and R⁸ areeach a hydrogen atom or a C₁₋₆ alkyl group.
 3. A medicine comprising asan effective ingredient the phenylene derivative or salt thereofaccording to claim 1 or
 2. 4. The medicine according to claim 3, whichis a curative for an allergic disease.
 5. The medicine according toclaim 3, which is a curative for a disease selected from asthma,allergic rhinitis, allergic conjunctivitis, atopic dermatitis,urticaria, psoriasis, rheumatism, inflammatory colitis, cerebralischemia or cerebral apoplexy.
 6. A medicinal composition comprising thephenylene derivative or salt thereof according to claim 1 or 2 and apharmacologically acceptable carrier.
 7. a method for curing a diseaseselected from asthma, allergic rhinitis, allergic conjunctivitis, atopicdermatitis, urticaria, psoriasis, rheumatism, inflammatory colitis,cerebral ischemia or cerebral apoplexy, which comprises administering aneffective amount of the phenylene derivative or salt thereof accordingto claim 1 or 2 to a patient.
 8. A method for treating an allergicdisease, which comprises administering an effective amount of thephenylene derivative or salt thereof according to claim 1 or 2 to apatient.
 9. A method for treating a disease selected from asthma,allergic rhinitis, allergic conjunctivitis, atopic dermatitis,urticaria, psoriasis, rheumatism, inflammatory colitis, cerebralischemia or cerebral apoplexy, which comprises administering aneffective amount of the phenylene derivative or salt thereof accordingto claim 1 or 2 to a patient.
 10. A method for curing an allergicdisease, which comprises administering an effective amount of thephenylene derivative or salt thereof according to claim 1 or 2 to apatient.